Parent Grant Summary: Effects of NPY on Hippocampal Circuit Function (5R01MH180342-04; PI:Dobrunz). The main objective of the parent grant is to investigate the mechanisms by which the abundantly expressed neuropeptide, Neuropeptide Y (NPY), modulates hippocampal circuit function to affect anxiety behavior, potentially leading to new therapeutic targets aimed at increasing NPY release to treat or prevent anxiety. The overarching hypothesis is that NPY suppresses synaptic plasticity in the temporammonic (TA) pathway to CA1, and that loss of NPY release in anxiety disorders alters hippocampal circuit function, contributing to maladaptive learning. Three interrelated specific aims focus on the properties of NPY cells and their inputs that determine synaptically-evoked spiking and trigger NPY release, effects of endogenously released NPY on excitatory and inhibitory synaptic transmission and plasticity, and the impact of stress-induced anxiety on endogenous NPY release at TA-CA1 synapses. Thus far, we have discovered heterogeneity in the properties of NPY cells that contribute to differences in synaptically-evoked spiking and NPY release, that NPY-containing neurogliaform cells in distal CA1 act as feed-forward interneurons and have properties that enable robust activation and NPY release, and that release of NPY dampens synaptic short-term facilitation at TA-CA1 synapses, providing critical circuit modulation in a pathway that regulates memory consolidation and fear learning. Finally, we discovered that NPY release is impaired in a rodent model of stress-induced anxiety, altering circuit function. Thus, we have developed a new experimental paradigm enabling the study of how endogenously released NPY modulates hippocampal circuits in health and disease states. SUPPLEMENT:NOT- AG-18-039 Alzheimer?s Disease and its related Dementias (AD/ADRD) NPY levels are reduced in patients with Alzheimer?s Disease (AD), and the number of NPY+ cells is decreased in postmortem AD hippocampal tissue. NPY has anti-anxiety and anti- depressant properties, and up to 50% of AD patients have anxiety and/or depression, suggesting a link to decreased NPY levels. Also relevant is the much greater risk of both AD and anxiety and depression in women, and importantly, estradiol increases NPY expression and release. Whether NPY release, anxiety and depression, AD, and heightened risk in females are connected has never been studied. Novel methods for measuring the effects of endogenously released NPY on hippocampal circuits developed in the PARENT R01 enables an investigation of the effects of NPY on hippocampal circuits in AD. In 2 specific aims, we will test the hypothesis that NPY levels are reduced in hippocampus of AD rats, and that loss of estrogen exacerbates this in females, leading to impaired release of NPY and altered hippocampal circuit function. We will leverage our expertise in studying endogenous NPY release and its effects on synaptic transmission, with the expertise of our collaborators in AD, sex differences, and in gene regulation, to begin to test this.